Cognitive and motor impairments seen in methamphetamine (METH) dependence are often unrelated to drug use parameters such as length of abstinence, lifetime consumption, chronicity, mode of delivery, etc. This suggests the possibility of individual differences in vulnerability to the neurotoxic effects of METH. The notion that some METH users develop NP impairments, while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of METH. While a number of candidate mechanisms need to be explored, one possible source of differential vulnerability to METH effects may be differences in METH metabolism. Cytochrome P450-2D6 (CYP2D6) and flavin-containing monooxygenase-3 FMO3 are involved in the oxidative metabolism of a number of psychoactive substances, including METH. Both have functional polymorphisms that affect their enzymatic activity, resulting in different rates of metabolism. We have evidence that METH dependent study participants with the extensive (wildtype) metabolizer CYP2D6 phenotype were three times as likely to manifest cognitive impairments compared to those with phenotypes corresponding to lower metabolic efficiency (intermediate and poor metabolizers), even though all had comparable METH exposure parameters. This implicates metabolite formation, perhaps above the parent substance itself, as a source of METH neurotoxicity. We therefore propose to examine the relationship between CYP2D6 and FMO3 genotypes and neuropathologic changes observed in brain tissue from METH dependent subjects who died with AIDS. We propose apply well-validated methods of stereological analysis to detect evidence of synaptodendritic simplication in brain regions known to be affected by METH, as well as measure evidence of oxidative stress. We will utilize brain tissue banked at the National NeuroAIDS Tissue Consortium from patients who received extensive antemortem neuomedical and neurobehavioral characterization. We predict that subjects whose genotypes correspond to higher levels of METH metabolism will have had higher levels of neurocognitive dysfunction during life as well as greater evidence of neuropathologic changes observed postmortem. To our knowledge, this is the first investigation of this type. The data collected, combined with our preliminary clinical data, would then be used in support of an application for a larger study of genetic determinants of vulnerability to METH-related brain injury. PUBLIC HEALTH RELEVANCE: Neurobehavioral deficits seen in methamphetamine (METH) dependence are often unrelated to drug use parameters, suggesting the possibility of individual differences in vulnerability to the neurotoxic effects of METH. We propose to examine the relationship between genetic differences in METH metabolism by cytochrome P450-2D6 (CYP2D6) and flavin-containing monooxygenase-3 (FMO3), cognitive impairment, and evidence of postmortem brain injury. The information gathered can help to uncover mechanisms of differential vulnerability to neural injury caused by repeated METH exposure.